SPECIFIC HYPORESPONSIVENESS OF ALLOREACTIVE PERIPHERAL T-CELLS INDUCED BY CD4 ANTIBODIES

We investigated whether exposure of naive and in vitro pre-activated T cells to CD4 monoclonal antibodies (mAb) could induce specific hypore sponsiveness to a subsequent challenge in the absence of CD4 mAb. Unfr actionated peripheral blood mononuclear cells were cultured with mitom ycin-treated B cell lines as stimulator cells, in the presence or abse nce of CD4 mAb, then challenged with the same or unrelated stimulator cells. The kinetics of [H-3] thymidine incorporation, blast transforma tion and CD25 expression were determined. Cells activated in primary o r secondary culture in the presence of CD4 mAb demonstrated a markedly decreased response to subsequent challenge in the absence of antibody . This effect was reproduced with three different CD4 mAb of the IgG(1 ) and IgG(2a) subclasses, which recognize two distinct epitopes of the CD4 molecule. Addition of recombinant interleukin-2 (rIL-2) during ex posure to CD4 mAb failed to prevent the induction of specific hyporesp onsiveness. Similarly, exogenous rIL-2, added together with stimulatin g cells, failed to restore the specific proliferative response, indica ting that the mechanisms were different from those of classical anergy . The hyporesponsiveness was clonally restricted since CD4 mAb-pretrea ted cells developed a normal primary response to third-party stimulato r cells. No increase in the percentage of apoptotic cells was observed in hyporesponsive cell populations, but selective clonal deletion can not be excluded. The data demonstrate a delayed effect of CD4 ligation on T cell responses to a subsequent challenge.